PROJECT SUMMARY/ABSTRACT Every year, more than 161,000 men in the U.S. are diagnosed with prostate cancer. While prostate cancer remains a significant cause of cancer related mortality, early screening efforts are hampered by the fact that the majority of cases are not imminently deadly and active treatments or re-biopsies have adverse side effects. The goal of this proposal is to pioneer new non-invasive diagnostics to distinguish between high-risk versus low-risk prostate cancers in order to guide clinical management. The core hypothesis of this proposal is that copy number variations and methylation markers can be found non-invasively in circulating nucleic acids as a surrogate for invasive tissue markers, and these markers can risk stratify localized prostate cancers. The first aim will evaluate two non-invasive biomarkers for prostate cancer using next-generation sequencing (NGS)-based approaches. Plasma and urine samples will be tested for copy number variations and methylation markers, and compared against concurrent prostate cancer tissue taken from prostate surgery. The second aim will evaluate the non-invasive approaches in the first aim for the ability to risk stratify localized prostate cancer in a cross-sectional study. In this K08 Mentored Clinical Scientist Research Career Development Award application, the applicant, Wei Gu, MD, PhD, is a board certified Clinical Pathologist at UCSF Department of Laboratory Medicine. This proposal encompasses a five-year plan to enhance his research and professional skills with the goal of becoming an independent physician-scientist focused on advancing non-invasive testing using cell-free nucleic acids as cancer biomarkers. Essential components of the career development plan are: (1) mentorship from a multidisciplinary team of scientists and physician-scientists with expertise in advanced molecular techniques, bioinformatics, biostatistics, and clinical study design; (2) formal didactics to expand on knowledge in clinical study design, cancer biology, bioinformatics, and professional development; (3) laboratory testing and analysis of cell-free DNA as biomarkers for prostate cancer; (4) professional development in the transition to independence, and (5) data collection for an R01 application. A mentorship and multidisciplinary scientific committee has been assembled to facilitate the proposal aims and progression towards independence. This plan will be implemented at University of California, San Francisco, which provides an exceptional research environment, state-of-art facilities, and a supportive scientific community that will be an ideal environment to foster career development and project success.